No abstract

Overproduction of nitric oxide and activation of soluble guanylate cyclase (sGC) are important in sepsis-induced hypotension and hyporesponsiveness to vasoconstrictors. A time course of the expression and activity of sGC in a sepsis model [cecal ligation and puncture (CLP)] was evaluated in rats. Soluble GC ␣-1 and ␤-1 subunit mRNA levels increased in the lungs, but not in the aorta. However, in both tissues, the protein levels increased 24 h after sepsis and remained high for up to 48 h. Sodium nitroprusside-stimulated cGMP accumulation was higher 48 h after CLP in the lung and aorta. NOS-2 protein expression peaked 24 h after CLP, decreasing thereafter. The impact of inhibiting the expression of sGC early (8 h) or late (20 h) on vascular reactivity and the indexes of organ damage and mortality were also studied. Late administration of methylene blue (MB) or ODQ (1H-[1,2,4]-oxadiazole[4,3-a]quinoxalin-1-one) restored the blood pressure and vascular responsiveness to vasoconstrictors to normal levels but was ineffective in early sepsis. Late MB injection reduced the plasma levels of urea, creatinine, and lactate. MB improved the survival if administered late, but it increased the mortality when administrated early after sepsis onset. The increased sGC expression/ activity may be relevant for the late hypotension and hyporesponsiveness to vasoconstrictors in sepsis. In accordance, MB increased survival if administered in late sepsis, but not in early sepsis. Therefore, differential responsiveness to sGC during the course of sepsis may determine the success or failure of treatment with sGC inhibitors.Severe sepsis and septic shock are major causes of mortality in intensive care units (Vincent et al., 2006). The number of patients with severe sepsis and septic shock is increasing because of increased life expectancy and the rise in the number of immunocompromised patients, among other reasons (Bonde et al., 2006).Large amounts of nitric oxide (NO) are produced by NO synthase (NOS) 2 (inducible NOS) isoform in response to an injury in the vascular endothelium (Chin-Wei et al., 2008), vascular smooth muscle (Rees et al., 1990), and myocardium (Niu et al., 2008). Increased NO production contributes to some of the key features of septic shock, such as severe hypotension, vascular hyporesponsiveness toward vasoconstrictors, and myocardial dysfunction. NOS inhibition studies in sepsis are mostly based on in vitro or animal studies (for review, see Assreuy, 2006). To date, all the NOS inhibitors that have been tested in the clinical setting are nonselective for the three NOS isoforms, which causes undesired side effects, such as excessive vasoconstriction, which was the most likely reason for a phase III study with a NOS inhibitor in human sepsis to be interrupted (López et al., 2004).Soluble guanylate cyclase (sGC) is a key element in NO signaling. This enzyme is usually a heterodimer of ␣ and ␤ subunits, and it is activated by NO binding to its heme This work was supported by

Curcumin is a polyphenol obtained from the plant Curcuma longa (called turmeric) that displays several pharmacological activities, including anti-inflammatory, antioxidant, antimicrobial and antitumoral activity, but clinical use has been limited by its poor solubility in water and, consequently, minimal systemic bioavailability. We have therefore formulated the drug into nanocarrier systems in an attempt to improve its therapeutic properties. This study evaluates the effect of intraperitoneally administered nanocapsules containing curcumin on subcutaneous melanoma in mice inoculated with B16-F10 cells, and on the cytotoxicity activity against B16-F10 cells in vitro. Phagocytic uptake of formulations was also evaluated upon incubation with macrophage J774 cells by fluorescence microscopy. Lipid and polymeric nanocapsules were prepared by the phase inversion and nanoprecipitation methods, respectively. The uptake of the lipid nanocapsules prepared using Solutol HS15 was significantly reduced in J774 cells. Curcumin, as free drug or as drug-loaded nanocapsules, was administrated at a dose of 6 mg/kg twice a week for 21 days. Free drug and curcuminloaded nanocapsules significantly reduced tumor volume (P < 0.05 vs. control), but no difference was found in the antitumor activity displayed by lipid and polymeric nanocapsules. This assumption was supported by the in vitro study, in which free curcumin as well as loaded into nanocapsules caused significant reduction of cell viability in a concentration-and time-dependent manner.

No abstract

No abstract